恩替卡韦治疗拉米夫定失效慢性乙型肝炎的临床观察

Entecavir for treatment of lamivudine-refractory chronic hepatitis B

目的观察恩替卡韦(ETV)治疗拉米夫定失效慢性乙型肝炎(CHB)的病毒学应答和耐药情况。方法对接受口服ETV(1.0mg/d,治疗疗程>12个月,基线HBVDNA≥104拷贝/ml)治疗的拉米夫定失效的41例CHB患者进行临床随访,定期检测其血清HBVDNA定量、乙型肝炎病毒标志物、肝功能及耐药情况。耐药检测采用半巢式PCR,对PCR产物进行直接测序,测序结果与GenBank报道的HBV序列进行同源性比对以检测ETV的耐药变异位点。结果41例患者接受ETV1.0mg/d治疗12个月时,39%(16/41)的患者HBVDNA转阴(<103拷贝/ml),64%基线ALT水平异常的患者ALT水平恢复正常(<40U/L),2名(7.7%)HBeAg阳性患者分别在治疗第10、12个月时获得HBeAg血清学转换。1例患者发生了ETV基因型耐药变异,耐药位点为rtL180M+rtM204V+rtS202G,该患者的基线血清中可检测到拉米夫定耐药突变(rtL180M+rtM204V)。结论ETV(1.0mg/d)治疗拉米夫定失效CHB有效,但应警惕耐药变异的发生。

Objective To characterize the virological and serological responses and drug resistance profile of entecavir used for treatment of lamivudine-refractory chronic hepatitis B （CHB） patients. Methods Patients of CHB who had prior received lamivudine treatment and developed lamivudine resistance before switched to oral administration of entecavir （1.0mg/d, monotherapy 〉12 months, baseline serum HBV DNA ≥104copies/ml） were prospectively followed. Virological and serologic responses and laboratory data of liver and renal function of each patient enrolled were monitored every three months. Entecavir resistant mutations were detected by direct sequencing of HBV reverse transcriptase region which was amplified by semi-nested polymerase chain reaction （PCR）. HBV sequences of different genotypes obtained from GenBank were aligned to identify entecavir drug resistant substitutions. Results Of the 41 lamivudine refractory CHB patients who met the inclusion criteria, 16 patients （39%） achieved the point of undetectability in HBV DNA level （〈103copies/ml） after 12 months of enticavir therapy with a dose of 1.0mg/d. In the 28 patients who had abnormal baseline ALT levels, the percentage of baseline ALT level normalization （〈40U/L） was 64%. Two of twenty six HBeAg-positve patients （7.7%） achieved HBeAg seroconversion in 10 and 12 months, respectively. Entecavir genotypic resistance was detected in one patient with resistant substitutions at rt180M＋rtM204V＋rtS202G of HBV reverse transcriptase region in whom pre-existing lamivudine genotypic resistant mutant （rtL180M＋rtM204V） could be detected from baseline serum. Conclusion Entecavir therapy with a dosage of 1.0mg/d is effective in treating lamivudine-refractory CHB patients, and careful monitoring for drug resistance should be performed.